In recent years, sodium-glucose cotransporter type 2 (SGLT-2) inhibitors, a class of medications originally developed for managing type 2 diabetes mellitus (T2DM), have demonstrated significant benefits beyond glycemic control. These drugs have shown protective effects on both renal and cardiovascular systems, even in patients without diabetes. Researchers suggests that metabolic reprogramming plays a critical role in the progression of chronic heart failure (CHF) and chronic kidney disease (CKD). This reprogramming is associated with impaired cardiac energy metabolism due to a mismatch between glucose uptake and its oxidation, leading to the accumulation of glucose-6-phosphate (G6P), glycogen deposition, and activation of the pentose phosphate pathway. The consequence is mitochondrial dysfunction, oxidative stress and decreased fatty acid oxidation.

Similar mechanisms occur in the proximal tubules of the kidneys in CKD, resulting in tubular injury, albuminuria, and interstitial fibrosis. By inhibiting glucose and sodium reabsorption in the proximal tubules, SGLT-2 inhibitors increase glucosuria, induce mild osmotic diuresis and promote natriuresis. These processes yield anti-inflammatory effects, reduce oxidative stress and apoptosis, and further stimulate autophagy.

The additional effects include lowered blood pressure, decreased myocardial workload and reduced sympathetic nervous system activity. Additionally, SGLT-2 inhibitors improve tubuloglomerular feedback, reduce glomerular hyperfiltration and enhance erythropoiesis by mimicking systemic hypoxia. These mechanisms form the basis of the cardio- and nephroprotective effects of SGLT-2 inhibitors.

Heart failure, chronic kidney disease, metabolic syndrome

Виноградова Н. Г., Поляков Д. С., Фомин И. В. Анализ смертности у пациентов с ХСН после декомпенсации при длительном наблюдении в условиях специализированной медицинской помощи и в реальной клинической практике. Кардиология. 2020;60(4):91-100. DOI:10.18087/cardio.2020.4.n1014.

Курочкина О. Н., Баранов А. В., Сажина А. С. и др. Современные методы лечения пожилых пациентов с хронической сердечной недостаточностью: обзор литературы. Фарматека. 2023;30(1-2):94-99. DOI:10.18565/pharmateca.2023.1-2.94-99.

Курочкина О. Н., Баранов А. В., Сажина А. С. и др. Возможности организации оказания медицинской помощи пациентам с хронической сердечной недостаточностью в регионах России с низкой плотностью населения. Профилактическая медицина. 2023;26(5):102-109. DOI:10.17116/ profmed202326051102.

Cowie MR, Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol. 2020;17(12):761-772. DOI:10. 1038/s41569-020-0406-8.

Vallon V, Verma S. Effects of SGLT2 inhibitors on kidney and cardiovascular function. Annu Rev Physiol. 2021;83:503-528. DOI:10.1146/annurev- physiol- 031620-095920.

American Diabetes Association Professional Practice Committee. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022 Jan 01;45(Suppl 1):S125-S143. Heerspink, H. J. L., Stefánsson, B. V., Correa-Rotter, R., Chertow, G. M., Greene, T., Hou, F. F., ... & DAPA-CKD Trial Committees and Investigators. (2020). Dapagliflozin in patients with chronic kidney disease. New England Journal of Medicine, 383(15), 1436–1446. https://doi.org/10.1056/NEJMoa2024816

Rhanderson Cardoso et al. SGLT2 inhibitors decrease cardiovascular death and heart failure hospitalizations in patients with heart failure: A systematic review and meta-analysis. EClinicalMedicine. 2021 Jun 5:36:100933.DOI: 10.1016/j.eclinm.2021.100933

Lopaschuk GD, Karwi QG, Tian R, et al. Cardiac energy metabolism in heart failure. Circ Res. 2021;128(10):1487-1513. DOI:10.1161/CIRCRESAHA. 121.318241.

Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol. 2018;19(2):121-135. DOI:10.1038/nrm. 2017.95.

Fontecha- Barriuso M, Martin- Sanchez D, Martinez- Moreno JM, et al. The role of PGC-1α and mitochondrial biogenesis in kidney diseases. Biomolecules. 2020;10(2):347. DOI:10.3390/biom10020347.

Vlado Perkovic et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019;380:2295-2306 DOI: 10.1056/NEJMoa1811744 VOL. 380 NO. 24

Hiddo J.L. et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med 2020;383:1436-1446 DOI: 10.1056/NEJMoa2024816

Fontecha- Barriuso M, Martin- Sanchez D, Martinez- Moreno JM, et al. The role of PGC-1α and mitochondrial biogenesis in kidney diseases. Biomolecules. 2020;10(2):347. DOI:10.3390/biom10020347.

Hiddo J L Heerspink et al. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications. Circulation. 2016 Sep 6;134(10):752-72. doi: 10.1161/CIRCULATIONAHA.116.021887.

Holcombe J, Weavers H. Functional- metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing. Nat Commun. 2023;14(1):8405. DOI:10.1038/s41467-023-44098-x.

Cherney, D. Z. I., & Lund, S. S. (2020). Perceptions and real-world experience with SGLT2 inhibitors: Translating the EMPA-REG OUTCOME and other trial results into clinical practice. Diabetologia, 63(10), 2131–2135. https://doi.org/10.1007/s00125-020-05229-6

Zinman, B., Wanner, C., Lachin, J. M., Fitchett, D., Bluhmki, E., Hantel, S., ... & EMPA-REG OUTCOME Investigators. (2015). Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New England Journal of Medicine, 373(22), 2117–2128. https://doi.org/10.1056/NEJMoa1504720

Lidan Yang, Lin Zhang, He He, Mei Zhang & Zhenmei An. Efficacy and Safety of Sodium-Glucose Cotransporter 2 Inhibitors in East Asians with Type 2 Diabetes: A Systematic Review and Meta-Analysis. Volume 10, pages 1921–1934, (2019)

Sukhjinder Chauhan et al. Empagliflozin-Associated Euglycemic Diabetic Ketoacidosis Masked by Urinary Tract Infection. Cureus. 2024 Aug 7;16(8):e66408. doi: 10.7759/cureus.66408.

Jiali Liu et al. Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis. Sci Rep. 2017 Jun 6;7(1):2824. DOI: 10.1038/s41598-017-02733-w.